Due to the lack of port-wine stain (PWS) lesion information, there is a fundamental gap in achieving the optimum therapeutic outcome of laser treatment of PWS in children. The existence of this gap for the past 30 years represents a long-standing clinical problem, and urgently demands a smart PWS laser treatment system that can optimize the outcome for an individual patient. The long term goal is to develop a smart, imaging technology guided PWS laser treatment system that uses computer models and three-dimensional PWS imaging results to generate optimized and individualized laser treatment parameters. The objective of this proposal, which is the first step in a continuum of research for solving the long-standing PWS clinical problem, is to combine current PWS laser treatment systems with an innovative imaging subsystem and intelligent software to predict therapeutic response. The rationale for the proposed research is that, once the above objective is achieved, the treatment of an individual patient by current laser treatment systems can be optimized, and novel PWS laser treatment systems and strategies can be designed for even better outcomes. To accomplish the objective of this proposal, the following three specific aims are proposed: 1) Develop an innovative transcutaneous PWS imaging system that can provide high-resolution, background-free, three- dimensional PWS vasculature images (mentored K99 phase); 2) Develop algorithms to derive quantitative PWS lesion information and computer models to predict treatment response (independent R00 phase); and 3) Develop an optimized, transcutaneous, multimodality PWS imaging system and conduct a pilot PWS imaging clinical study (independent R00 phase). Under the first aim, an innovative PWS imaging system based on the recently developed optical-resolution photoacoustic microscopy (OR-PAM) will be developed and tested in the clinic. Under the second aim, imaging processing algorithms will be used to extract quantitative PWS lesion information from the PWS images, and computer modeling methods will be developed for predicting the therapeutic response. Under the third aim, a multimodality PWS imaging system that combines both the tissue structure imaging capability of optical coherence tomography and the PWS vasculature imaging capability of OR-PAM will be developed, optimized, and clinically tested. The approach is innovative because it utilizes the recently developed OR-PAM imaging technology to remove the technology barriers faced by current PWS imaging modalities. The proposed research is significant because it provides fundamental missing components in current PWS laser treatment, and represents the first step in a continuum of research that is expected to lead to solving the long-standing PWS clinical problem. Additionally, the proposed K99/R00 research work will prepare the applicant as an independent investigator in the field of laser treatment of vasculature-related skin diseases, particularly PWS in children.